mRNA展示技术高通量筛选环肽药物的研究进展
收稿日期: 2025-08-13
修回日期: 2025-10-20
网络出版日期: 2025-10-31
基金资助
国家自然科学基金项目(82573711);国家自然科学基金项目(22407052);江苏省自然科学基金(BK20240300);江苏省卫健委科研项目(MQ2024007);江苏省卫健委科研项目(H2023150);江苏省卫健委科研项目(K2024007);无锡市科技发展基金(K20241060);无锡市卫健委重大项目(Z202303);无锡科学技术协会(TJXD-2024-102)
Advances in high-throughput screening of cyclic peptide drugs using mRNA display technology
Received date: 2025-08-13
Revised date: 2025-10-20
Online published: 2025-10-31
Supported by
National Natural Science Foundation of China(82573711);National Natural Science Foundation of China(22407052);Natural Science Foundation of Jiangsu Province(BK20240300);Scientific Research Projects of Jiangsu Health Commission(MQ2024007);Scientific Research Projects of Jiangsu Health Commission(H2023150);Scientific Research Projects of Jiangsu Health Commission(K2024007);Wuxi Science and Technology Development Fund(K20241060);Major Project of Wuxi Municipal Health Commission(Z202303);Wuxi Association for Science and Technology(TJXD-2024-102)
环肽作为突破传统药物开发“难以成药”靶点的重要分子形式，凭借其独特的构象约束特性，成功弥补了小分子药物与生物制剂的治疗间隙。尽管早期环肽的发现依赖于天然产物的挖掘，但是展示技术的出现将库容量提升至1015，加速了全新环肽药物的研发。mRNA展示技术作为一种基因型(mRNA)与表型(蛋白质)融合的体外多肽/蛋白质筛选技术，可在一次实验中筛选数万亿蛋白质变体以实现所需功能。近年来，随着利用mRNA展示技术筛选出的多肽药物进入临床研发阶段，从头开始的环肽药物发现领域逐渐走向成熟。本文对mRNA展示技术的原理、特点以及其在环肽药物研发过程中的应用展开综述，以期为推动基于mRNA展示技术的原创性环肽药物发现提供新的思路和策略借鉴。
王爽, 朱雪, 方晶, 薛岩, 黄志洪, 王柯 . mRNA展示技术高通量筛选环肽药物的研究进展[J]. 遗传, 2026 , 48(4) : 345 -354 . DOI: 10.16288/j.yczz.25-186
Cyclic peptides have emerged as a promising therapeutic modality for targeting classically deemed “undruggable” protein that defy conventional small-molecule intervention. Their rigid conformations improve binding affinity, selectivity and proteolytic stability, bridging the gap between low-molecular-weight drugs and large biologics. Early discovery of cyclic peptide relied on natural product isolation. However, display technologies now enable the generation and screening of libraries containing up to 1015 unique sequences. Among these, mRNA display technology offers a uniquely powerful in vitro platform that covalently links genotype (mRNA) to phenotype (encoded peptide), facilitating the ultrahigh-throughput interrogation of trillions of variants in a single selection cycle. Recent clinical translation of de novo mRNA display-derived cyclic peptides signals the approach’s maturation. In this review, we systematically evaluate mRNA display technology by outlining its methodological framework and highlighting its unique advantages for engineering macrocyclic therapeutics. We critically examine its transformative potential as well as its inherent limitations in identifying bioactive cyclic peptides, with particular attention to library diversity and the precision of on-resin screening. Through this analysis, we aim to provide insightful perspectives and strategic recommendations to guide future efforts in exploiting mRNA display for the development of innovative cyclic peptide-based drugs.
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